Types of Cholangiocarcinoma

Transcription

1 Colangiocarcinoma

2 Types of Cholangiocarcinoma Peripheral Perihilar Distal 20-30% Intrahepatic mass Cirrhosis uncommon 40-60% Biliary confluence Most common 20-30% 10-15% of peripancreatic tumors

3 Epidemiology of Cholangiocarcinoma

4 Epidemiology of ICC Second most frequent primary liver tumor Increasing incidence and mortality worldwide Changes in age standardized mortality rate Khan SA, et al. Lancet 2005;366>1313

5 Etiology Cholangiocarcinoma Primary sclerosing cholangitis Mainly associated with pcc. Hepatobiliary flukes (40% ICC) Clonorchis sinensis and Opistorchis viverrini (OR up to 27) Biliary tract cysts Choledochal cystic disease types I and IV (OR: 10 to 37) Hepatholithiasis OR: 6 to 50 Hepatotoxins Nitrosamines

6 Relative Risk Etiology of ICC Cirrhosis Of any nature. Chronic viral hepatitis HBV and HCV. Obesity Diabetes Conflicting results. Alcohol Smoking ,8 8 3,6 2,6 1,6 Biliary Dis Cirrhosis DM HCV Smoking Chaiiteerakij D et al. Hepatology 2013; 57:648

7 Genetic variation and risk of cancer RISK FACTORS Cancer Patients Normal Individuals GENETIC DIFFERENCES A * Single nucleotide polymorphism (SNP) G *

8 Etiology of ICC Several genetic polymorphisms have been identified DNA preservation Toxin clearance Inflammation Bridgewater J, et al. J Hepatol 2014;60:1268

9 Oncogenes y Cáncer Survival Factors (e.g. IGF1) Chemokines, Hormones (e.g. Interleukins, serotonin) Growth Factors (e.g. TGF, EGF, HGF) RTK PI3K AKT mtor G Protein Adenylate cyclase PKA RTK RAS RAF MEK MEKK MAPK MKK GSK3b APC b-catenin WNT Cytokines (e.g. IFN) JAK STAT CREB STAT myc ERK JNK fos Gene regulation jun b-catenin Cyclin CDK p53 cell proliferation

10 Mecanismos de activación de oncogenes Normal gene Normal protein

11 Mecanismos de activación de oncogenes hyperactive growth-stimulating protein in normal amount normal growth-stimulating protein in excess gene mutation gene deletion gene amplification chromosome rearrangements novel regulatory sequences fusion transcripts normal growth-stimulating protein in excess hyperactive growth-stimulating protein in normal amount or excess

12 Cambios en la metilación y cáncer

13 Pathogenesis of ICC Sia D, et al. Oncogene 2013;32:4861

14 Molecular Classification of ICC Sia D, et al. Gastroenterology 2013; 144:829

15 Clinical Presentation of ICC Patients with early stage are usually asymptomatic. At more advanced stages, they may have non-specific symptoms weight loss, malaise, abdominal discomfort, night sweats, fever, or a palpable mass. Jaundice due to biliary tract obstruction is infrequent. CCA should be considered in patients with underlying disease (hepatolithiasis or PSC) with worsening performance status or unexplained loss of weight. Changes in liver function tests are non-specific, mainly with increased APh and GGT

16 Imaging of ICC Computed Tomography arterial portal venous

17 Imaging of ICC Magnetic Resonance T1 T2 arterial portal venous

18 Imaging of ICC arterial portal venous

19 Imaging of ICC T1 T2 DWI arterial portal venous

20 Imaging of ICC 25 patients with ICC on cirrosis. Median diameter 25 mm. Rimola J, et al. Hepatology 2009;50:791

21 Tumor Markers CA 19-9 has significant overlap with benign diseases. Sensitivity is 62% Specificity is 63% CA 19-9 has some prognostic power: Preoperative values > 100 U/ml are associated with worse RFS. Bile duct obstruction may affect CA 19-9 levels (it should be reassessed after biliary intervention or drainage).

22 Pathological Diagnosis Typically an adenocarcinoma with tubular and/or papillary structures and a variable fibrous stroma. Similar to metastatic adenocarcinoma especially those of foregut origin (lung, pancreas, esophagus, and stomach). The expression of CK7 and CK20 may be helpful to establish a biliary origin. Differentiation from mixed HCC tumors may require evaluation of specific markers of hepatocellular or progenitor cell features Hep-Par-1, GPC3, HSP70, GS, EpCAM, and CK19. Pathological diagnosis is required for definitive diagnosis, particularly those with cirrhosis and small hepatic mass lesions. recommended for all patients who will be undergoing systemic chemotherapy or radiation therapy, or enrolling in a therapeutic clinical trial.

23 Colangiocarcinoma Intrahepático Estadio I Estadio II Estadio III Estadio IV Tumor único Multiple Invasión vascular (IV) Perforación peritoneo visceral, Invasión hepática local Invasión periductal, N1M1

24 Colangiocarcinoma Intrahepático Estadio I Estadio II Estadio III Estadio IV Tumor único Multiple Invasión vascular (IV) Perforación peritoneo visceral, Invasión hepática local Invasión periductal, N1M1 Resecable (30-40 %) No resecable (60-70 %) Enfermedad sólo intrahepática Enfermedad extrahepática Resección curativa Resección no curativa Terapia Locorregional Terapia Sistémica Observación Ensayos Clínicos Supervivencia a 5 años R0: 40 % Supervivencia a 5 años N1 e IV: 20 % RF/TACE: mediana supervivencia 15 meses Quimioterapia: mediana supervivencia 12 meses Bridgewater J, et al. J Hepatol 2014;60:1268

25 Liver Transplantation ICC has been considered a contraindication to LT based on very poor outcomes in historical series However, very early tumors may have much better outcomes A retrospective cohort multicenter study in 16 Spanish transplant centers. 29 patients found to have an icca on pathology examination AND cirrhosis of etiologies other than PSC. Indication for LT: HCC, or liver dysfunction with pre-transplant identification of a liver nodule; incidental tumors also included. Sapisochin G, et al. Am J Transplant 2014; 14: 660

26 Liver Resection The main determinants of resectability are extrahepatic disease tumor number and location involvement of portal vein and bile ducts Resectability rates are 20-40% 535 resected patients ( ) Portal vein embolization may allow surgical rescue. Prolonged survival is infrequent, even in good surgical candidates. Spolverato G, et al. JAMA Surg. 2015;150:538

27 Liver Resection Multicenter, international, retrospective study 584 patients who underwent resection of ICC ( ) Spolverato G, et al. JAMA Surg. 2015;150:538

28 Transarterial Therapies

29 TACE for ICC

30 TACE for ICC Variable Burger Herber Schiffman Park No. of patients Drugs CDDP- DOX-MMC MMC DEBIRI CDDP ECOG > 0 53% 26% 35% Multifocal 29% 53% 87% 57% Chemo 35% 26% 80% 0 Resection 6% 29% 0 Tumor Response 47%* 6% 25% 23% Median survival from RE * EASL criteria

31 Radioembolization for ICC 3-months post-y90 Y90-PET/CT Before Y90 MAA-PET/CT

32 Radioembolization for ICC Variable Ibrahim Saxena Hoffman Rafi Mouli No. of patients ECOG > 0 58% 40% 49% 95% 48% Multifocal 54% 70% 68% 35% Burden < 25% 83% 40% 75% 78% Chemo 29% 72% 79% 100% 35% Resection 40% 36% 11% Tumor Response 27% 24% 36% 11% 25% Survival since RE

33 Systemic Chemotherapy Valle J, et al. N Engl J Med 2010;362:1273.

34 Systemic Chemotherapy Cisplatin (25 mg/m2) + Gemcitabine (1000 mg/m2) days 1 and 8 every 3 weeks is currently the standard of practice There is currently no targeted therapy which is applicable in CAA. There is no evidence which supports a second line chemotherapy Valle J, et al. N Engl J Med 2010;362:1273. Okusaka T, et al. Br J Cancer 2010;103:469. Eckel and Schmid. Br J Cancer 2007;96:896.

35 Targeted Agents Under Investigation Schweitzer and Vogel. Best Practice & Research Clinical Gastroenterology 2015, 29:345.